HYPERCALCEMIABabak Tamizi Far MD.Assistant professor of internal medicineAl-zahra hospital, Isfahan university ofmedical sciences

Babak Tamizi Far MD.Assistant professor of internal medicineAl-zahra hospital, Isfahan university ofmedical sciences

ESSENTIALS OF DIAGNOSIS

Serum calcium level > 10.5 mg/dL Serum ionized calcium > 5.3 mg/dL Primary hyperparathyroidism and malignancy-

associated hypercalcemia are the most commoncauses

Hypercalciuria usually precedes hypercalcemia Most often, asymptomatic, mild hypercalcemia (

11 mg/dL) is due to primaryhyperparathyroidism, whereas the symptomatic,severe hypercalcemia ( 14 mg/dL) is due tohypercalcemia of malignancy

Serum calcium level > 10.5 mg/dL Serum ionized calcium > 5.3 mg/dL Primary hyperparathyroidism and malignancy-

associated hypercalcemia are the most commoncauses

Hypercalciuria usually precedes hypercalcemia Most often, asymptomatic, mild hypercalcemia (

11 mg/dL) is due to primaryhyperparathyroidism, whereas the symptomatic,severe hypercalcemia ( 14 mg/dL) is due tohypercalcemia of malignancy

GENERAL CONSIDERATIONS

Primary hyperparathyroidism and malignancyaccount for 90% of cases

Chronic hypercalcemia (over 6 months) orsome other manifestations such asnephrolithiasis suggests a benign cause

Tumor production of PTH-related proteins(PTHrP) is the most common paraneoplasticendocrine syndrome, accounting for mostcases of hypercalcemia in inpatients

Primary hyperparathyroidism and malignancyaccount for 90% of cases

Chronic hypercalcemia (over 6 months) orsome other manifestations such asnephrolithiasis suggests a benign cause

Tumor production of PTH-related proteins(PTHrP) is the most common paraneoplasticendocrine syndrome, accounting for mostcases of hypercalcemia in inpatients

Granulomatous diseases, such assarcoidosis and tuberculosis, causehypercalcemia from production of activevitamin D3 (1,25 dihydroxyvitamin D3) bythe granulomas

Milk-alkali syndrome has had aresurgence related to calcium ingestionfor prevention of osteoporosis

GENERAL CONSIDERATIONS

Granulomatous diseases, such assarcoidosis and tuberculosis, causehypercalcemia from production of activevitamin D3 (1,25 dihydroxyvitamin D3) bythe granulomas

Milk-alkali syndrome has had aresurgence related to calcium ingestionfor prevention of osteoporosis

Etiology

Increased intake or absorption Milk-alkali syndrome Vitamin D or A excess

Endocrine disorders Primary and secondary hyperparathyroidism Acromegaly Adrenal insufficiency Pheochromocytoma Thyrotoxicosis

Increased intake or absorption Milk-alkali syndrome Vitamin D or A excess

Endocrine disorders Primary and secondary hyperparathyroidism Acromegaly Adrenal insufficiency Pheochromocytoma Thyrotoxicosis

Neoplastic diseases Tumor production of PTHrP (ovary, kidney,

lung) Multiple myeloma (osteoclast-activating

factor) Lymphoma

Etiology

Neoplastic diseases Tumor production of PTHrP (ovary, kidney,

lung) Multiple myeloma (osteoclast-activating

factor) Lymphoma

Miscellaneous causes Thiazide diuretics Granulomatous diseases Paget bone disease Hypophosphatasia Immobilization Familial hypocalciuric hypercalcemia Complications of kidney transplantation Lithium intake

Etiology

Miscellaneous causes Thiazide diuretics Granulomatous diseases Paget bone disease Hypophosphatasia Immobilization Familial hypocalciuric hypercalcemia Complications of kidney transplantation Lithium intake

Clinical FindingsSYMPTOMS AND SIGNS

May affect gastrointestinal, kidney, andneurologic function

Mild hypercalcemia is oftenasymptomatic

Symptoms usually occur if the serumcalcium is > 12 mg/dL and tend to bemore severe if hypercalcemia developsacutely

May affect gastrointestinal, kidney, andneurologic function

Mild hypercalcemia is oftenasymptomatic

Symptoms usually occur if the serumcalcium is > 12 mg/dL and tend to bemore severe if hypercalcemia developsacutely

SYMPTOMS AND SIGNS

Constipation and polyuria Polyuria is absent in hypocalciuric

hypercalcemia Polyuria from hypercalciuria-induced

nephrogenic diabetes insipidus canresult in volume depletion and acutekidney injury

Constipation and polyuria Polyuria is absent in hypocalciuric

hypercalcemia Polyuria from hypercalciuria-induced

nephrogenic diabetes insipidus canresult in volume depletion and acutekidney injury

Other abdominal symptoms include

Nausea Vomiting Anorexia Peptic ulcer disease Renal colic Hematuria from nephrolithiasis

Nausea Vomiting Anorexia Peptic ulcer disease Renal colic Hematuria from nephrolithiasis

Neurologic manifestations may rangefrom mild drowsiness to weakness,depression, lethargy, stupor, and comain severe cases

Ventricular ectopy and idioventricularrhythm occur and can be accentuated bydigitalis

Neurologic manifestations may rangefrom mild drowsiness to weakness,depression, lethargy, stupor, and comain severe cases

Ventricular ectopy and idioventricularrhythm occur and can be accentuated bydigitalis

DiagnosisLABORATORY TESTS

Serum calcium level > 10.5 mg/dL Serum ionized calcium > 5.3 mg/dL The highest serum calcium levels ( 15 mg/dL)

generally occur in malignancy A high serum chloride concentration and a low

serum phosphate concentration (ratio > 33:1)suggest primary hyperparathyroidism becausePTH decreases proximal tubular phosphatereabsorption

Serum calcium level > 10.5 mg/dL Serum ionized calcium > 5.3 mg/dL The highest serum calcium levels ( 15 mg/dL)

generally occur in malignancy A high serum chloride concentration and a low

serum phosphate concentration (ratio > 33:1)suggest primary hyperparathyroidism becausePTH decreases proximal tubular phosphatereabsorption

LABORATORY TESTS

Urinary calcium excretion > 200 mg/day suggests hypercalciuria < 100 mg/day suggests hypocalciuria

Hypercalciuria from malignancy or fromvitamin D therapy frequently results inhypercalcemia when volume depletion occurs

Measurements of PTH and PTHrP levels helpdistinguish between hyperparathyroidism(elevated PTH) and malignancy-associatedhypercalcemia (suppressed PTH and elevatedPTHrP)

Serum phosphate may or may not be low,depending on the cause

LABORATORY TESTS

Hypercalciuria from malignancy or fromvitamin D therapy frequently results inhypercalcemia when volume depletion occurs

Measurements of PTH and PTHrP levels helpdistinguish between hyperparathyroidism(elevated PTH) and malignancy-associatedhypercalcemia (suppressed PTH and elevatedPTHrP)

Serum phosphate may or may not be low,depending on the cause

IMAGING STUDIES

Chest radiograph: to exclude malignancy orgranulomatous disease

DIAGNOSTIC PROCEDURE ECG: shortened QT interval

Chest radiograph: to exclude malignancy orgranulomatous disease

DIAGNOSTIC PROCEDURE ECG: shortened QT interval

Treatment: MEDICATIONSEmergency treatment

Establish euvolemia to induce renal excretionof Na+, which is accompanied by excretion ofCa2+

In dehydrated patients with normal cardiac andrenal function, infuse 0.45% saline or 0.9%saline rapidly (250–500 mL/h)

Furosemide intravenously is oftenadministered but its efficacy and safety werequestioned in one meta-analysis

Establish euvolemia to induce renal excretionof Na+, which is accompanied by excretion ofCa2+

In dehydrated patients with normal cardiac andrenal function, infuse 0.45% saline or 0.9%saline rapidly (250–500 mL/h)

Furosemide intravenously is oftenadministered but its efficacy and safety werequestioned in one meta-analysis

Emergency treatment

Thiazides can actually worsenhypercalcemia (as can furosemide ifinadequate saline is given

In the treatment of hypercalcemia ofmalignancy

Bisphosphonates are the mainstay,although they may require up to 48–72hours before reaching full therapeuticeffect

Calcitonin may be helpful to treathypercalcemia before the onset of actionof bisphosphonates

Bisphosphonates are the mainstay,although they may require up to 48–72hours before reaching full therapeuticeffect

Calcitonin may be helpful to treathypercalcemia before the onset of actionof bisphosphonates

THERAPEUTIC PROCEDURES

In emergency cases, dialysis with low orno calcium dialysate may be needed

In emergency cases, dialysis with low orno calcium dialysate may be needed

Table 347-2 Guidelines for Parathyroid Surgery inAsymptomatic Primary Hyperparathyroidisma

Measurement Guidelines, 1990 Guidelines, 2002

Serum calcium (aboveupper limit of normal)

0.3–0.4 mmol/L(1–1.5mg/dL) above normal

0.3 mmol/L (1.0mg/dL) above normal

24-h urinary calcium >400 mg >400 mg24-h urinary calcium >400 mg >400 mg

Creatinine clearance Reduced by 30% Reduced by 30%

Bone mineral density Z-score <-2.0 (forearm) T-score <-2.5 at anysite

Age <50 <50

OutcomeFOLLOW-UP

Monitor serum calcium at least every 6months during medical therapy ofhyperparathyroidism

COMPLICATIONS

Pathologic fractures Renal calculi Chronic kidney disease Peptic ulcer disease Pancreatitis Precipitation of calcium throughout the

soft tissues Gestational hypercalcemia produces

neonatal hypocalcemia

Pathologic fractures Renal calculi Chronic kidney disease Peptic ulcer disease Pancreatitis Precipitation of calcium throughout the

soft tissues Gestational hypercalcemia produces

neonatal hypocalcemia

PROGNOSIS

Depends on the underlying disease Poor prognosis in malignancy Depends on the underlying disease Poor prognosis in malignancy

PREVENTION

Prevent dehydration that can furtheraggravate hypercalcemia

WHEN TO REFER

Patients with malignancy-relatedhypercalcemia should be referred to anoncologist

Patients with endocrine disorders should bereferred to an endocrinologist

Patients with granulomatous diseases (eg,tuberculosis and other chronic infections,Wegener granulomatosis, sarcoidosis) mayrequire consultation with infectious diseasespecialists, rheumatologists, or pulmonologists

Patients with malignancy-relatedhypercalcemia should be referred to anoncologist

Patients with endocrine disorders should bereferred to an endocrinologist

Patients with granulomatous diseases (eg,tuberculosis and other chronic infections,Wegener granulomatosis, sarcoidosis) mayrequire consultation with infectious diseasespecialists, rheumatologists, or pulmonologists

WHEN TO ADMIT

Patients with symptomatic or severehypercalcemia require immediatetreatment

Unexplained hypercalcemia withassociated conditions, such as acutekidney injury or suspected malignancy,may also require hospitalization fortreatment and expedited evaluation

Patients with symptomatic or severehypercalcemia require immediatetreatment

Unexplained hypercalcemia withassociated conditions, such as acutekidney injury or suspected malignancy,may also require hospitalization fortreatment and expedited evaluation

The End